Multiply adjusted odds ratios (ORs) (99% confidence intervals [CIs]) for presenting with ST-segment elevation myocardial infarction (STEMI) vs non-STEMI. Results are shown for all men and women (total), for men and women separately, and by age for previous use of aspirin (A), β-blockers (B), angiotension-converting enzyme (ACE) inhibitors (C), and statins (D). To provide a more accurate presentation of the 99% CIs, ORs are represented on a linear scale after logarithmic transformation. The vertical dotted lines indicate the reference value.
Multiply adjusted odds ratios (ORs) (99% confidence intervals [CIs]) for presenting with ST-segment elevation myocardial infarction (STEMI) vs non-STEMI. Results are shown in relation to the number of medications being received before presentation (regardless of medication type). To provide a more accurate presentation of the 99% CI intervals, ORs are represented on a linear scale after logarithmic transformation. The vertical dotted line indicates the reference value.
Björck L, Wallentin L, Stenestrand U, Lappas G, Rosengren A. Medication in Relation to ST-Segment Elevation Myocardial Infarction in Patients With a First Myocardial InfarctionSwedish Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA). Arch Intern Med. 2010;170(15):1375–1381. doi:10.1001/archinternmed.2010.203
Copyright 2010 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2010
The extent and the severity of acute myocardial infarction (MI) is decreasing. Out-of-hospital medical management before the hospital admission could alter clinical presentation in acute MI. We used a large national patient register to investigate the relation between previous medication use (aspirin, β-blockers, angiotensin-converting enzyme [ACE] inhibitors, and statins) and the risk of presenting with ST-segment elevation MI (STEMI) or non-STEMI.
We included 103 459 consecutive patients from the Swedish Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA) admitted between January 1, 1996, and December 31, 2006, with a first acute MI.
The patients with STEMI (43.5% of the total) were younger, had less prior cardiovascular disease, and used fewer medications before hospitalization. Of the STEMI patients, 61.4% had used no medication vs 45.9% of the patients with non-STEMI. After multiple adjustments, use of aspirin, β-blockers, ACE inhibitors, and statins before hospitalization were all associated with substantially lower odds of presenting with STEMI. Furthermore, the risk decreased with the number of previous medications, and the use of 3 or more medications was associated with a multiply adjusted odds ratio of presenting with STEMI of 0.48 (99% confidence interval, 0.44-0.52) compared with no medications at admission.
Use of aspirin, β-blockers, ACE inhibitors, or statins before hospital admission in patients with a first acute MI is associated with substantially less risk of presenting with STEMI. The risk decreases with the increasing number of these medications used before acute MI, underlining the benefit of preventive medication in high-risk patients.
Coronary heart disease (CHD) mortality rates and incidence have decreased during the past few decades in most western countries, including Sweden.1- 3 In addition to decreasing CHD rates, there has been a shift over time in clinical presentation, with less severe and smaller acute myocardial infarctions (AMIs), more unstable angina pectoris, and lower case fatality rates.4
Risk factors for CHD are well known,5 and decreasing cholesterol levels and lower rates of smoking and other risk factors have contributed to the marked decrease in CHD mortality in many European and North American countries.6,7 In addition, medications used in the treatment of several cardiovascular conditions such as hypertension, angina, and heart failure have also contributed to the decrease in CHD mortality. Aspirin, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and statins have been found to reduce mortality due to cardiovascular disease in randomized controlled trials conducted in various subsets of patients. The extent to which medications influence clinical presentation in CHD has not been widely investigated. In 1 study, the use of statins and β-blockers was associated with a lower risk of presenting with MI compared with stable exertional angina.8 In patients with acute coronary syndromes (ACSs), the use of aspirin and statins has been associated with lower risk of presenting with ST-segment elevation as a marker of larger infarctions.9,10 Whether other pharmacological agents or medications in combination are also associated with a lower risk of presenting with ST-segment elevation MI (STEMI) is not known. We used data from a large national register of patients admitted to Swedish coronary care units to investigate the association between previous medication use (aspirin, β-blockers, ACE inhibitors, and statins) and clinical presentation (STEMI or non-STEMI) in patients with a first AMI.
The Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA) includes all patients admitted to hospitals with coronary care units. The full protocol has been published previously11 (detailed information and the complete protocol are also available at http://www.ucr.uu.se/rikshia/). RIKS-HIA started in 1995 with 19 participating hospitals, increasing gradually to 73 (of 77) Swedish hospitals in 2006. The present study is based on all consecutive patients aged 25 to 84 years without a history of AMI who were admitted to a hospital between January 1, 1996, and December 31, 2006, and discharged with a diagnosis of STEMI or non-STEMI.
The ST segment was recorded as the first choice of which the following alternatives accurately described the ST segment on the electrocardiogram at entry: 1 indicates normal; 2, left bundle branch block or pacemaker; 3, ST-segment elevation; 4, ST-segment depression; 5, T-wave inversion; and 6, other changes. The criteria for a diagnosis of AMI were standardized and identical for all participating hospitals using the World Health Organization, Joint European Society of Cardiology, and American College of Cardiology Committee criteria.12 We defined STEMI as presentation with ST-segment elevation. Information on medication was missing in less than 1% of patients. In cases with missing information, it was presumed that the patient did not use that particular drug. Because prior angina was only registered until 2003, we substituted use of medication with long-acting nitrates before admission as a proxy for previous angina. The use of aspirin includes aspirin sold over the counter. Use of angiotensin II receptor blockers was only recorded in 2004 to 2006 and was not included. Data on mortality were obtained by merging the RIKS-HIA with the Swedish National Cause of Death Register.
The RIKS-HIA was approved by an ethics committee and the National Board of Health and Welfare of Sweden. The process of merging mortality data with the Swedish National Cause of Death Register was approved by the ethics committee in Uppsala.
Baseline characteristics were summarized as means or percentages as appropriate. The independent associations between STEMI and previous use of aspirin, β-blockers, ACE inhibitors, or statins were assessed by means of logistic regression, in which STEMI was entered as the dependent variable and the following variables were used as covariates (possible confounders): age, sex, year of admission, medications before study entry (aspirin, β-blockers, ACE inhibitors, and statins), and history of smoking (never, current, and former), coronary artery bypass graft, percutaneous coronary intervention, diabetes mellitus, hypertension, heart failure, or angina. To investigate potential interactions between sex and previous medication use and between age and previous medication use, interaction terms (sex × previous medication use and age × previous medication use) were defined and introduced into the models. All statistical analyses were performed using commercially available software (SPSS, version 15.0; SPSS Inc, Chicago, Illinois). Odds ratios (ORs) were calculated from the logistic regression models. Because of the large population, 99% confidence intervals (CIs) were used.
Of 117 359 patients, we excluded 13 497 with left or right bundle branch block or pacemaker on the electrocardiogram. In addition, we excluded 403 patients with no recorded information of ST segment. However, including patients with left or right bundle branch block did not significantly change the results. After these exclusions, the final sample included 103 459 patients admitted to the hospital for a first AMI. Of those, 43.5% presented with STEMI and 56.5% with non-STEMI. During the study period, 30-day mortality in STEMI patients decreased from 13.0% in 1996 to 5.6% in 2006 and in non-STEMI patients from 10.9% in 1996 to 4.1% in 2006. One-year mortality decreased from 18.0% in both STEMI and non-STEMI patients to 8.8% in STEMI patients and 10.0% in non-STEMI patients.
Table 1 shows baseline characteristics in the STEMI and non-STEMI patients. Patients with STEMI were more often men and slightly younger than patients with non-STEMI. Moreover, smoking was more common: 31.1% of patients with STEMI were current smokers vs 23.7% of non-STEMI patients (P < .001). Patients with non-STEMI had significantly more hypertension, diabetes mellitus, heart failure, prior angina pectoris, and known cardiovascular disease with prior percutaneous coronary intervention or coronary artery bypass graft. Hence, use of aspirin, β-blockers, ACE inhibitors, and statins was more common in non-STEMI patients. All differences were statistically significant (P < .001).
In subsequent analyses, we compared the use of aspirin, β-blockers, ACE inhibitors, and statins before AMI in STEMI and non-STEMI patients. Patients with STEMI used aspirin (20.4% vs 33.5%), β-blockers (22.5% vs 33.2%), ACE inhibitors (10.3% vs 15.8%), and statins (8.1% vs 15.0%) less often than did non-STEMI patients before AMI (P < .001 for all; Table 1).
We used logistic regression in a multivariable model to investigate separately how the use of aspirin, β-blockers, ACE inhibitors, and statins before AMI affected the risk of presenting with STEMI. All models were adjusted for age, sex, hypertension, diabetes, heart failure, angina, prior revascularization, smoking, and year of admission and mutually for previous use of aspirin, β-blockers, ACE inhibitors, and statins. Overall, previous use of aspirin (multiply adjusted OR, 0.72; 99% CI, 0.69-0.76), β-blockers (0.82; 0.78-0.86), ACE inhibitors (0.84; 0.79-0.89), and statins (0.79; 0.74-0.84) were all independently associated with substantially lower risk of presenting with STEMI (Table 2). Next, we investigated the association of each medication separately in men and women and in the groups aged 25 to 64 years and 65 to 84 years for men and women (Figure 1). Effects were consistent for all 4 types of medication, with no suggestion of any interaction effects of age or sex. Of the 103 459 patients, 12 250 had prior coronary disease, including angina and/or revascularization procedures. Odds ratios associated with the 4 types of medication were broadly similar irrespective of the presence or absence of prior coronary disease (data not shown).
Table 3 compares characteristics in patients with no, 1, 2, or 3 or more medications, irrespective of type of medication. As expected, patients with more medications had more comorbidities and notably higher rates of hypertension and diabetes but also of heart failure and prior revascularization. A higher proportion of patients with STEMI were receiving no medication before AMI (61.4% for STEMI patients vs 45.9% for non-STEMI patients) (Table 4). Conversely, a lower proportion of STEMI patients had 3 or more medications (4.9% for STEMI patients vs 11.1% for non-STEMI patients). After adjustment for comorbidities and other factors, use of 1 medication, regardless of type, was associated with lower risk of presenting with STEMI (multiply adjusted OR, 0.76; 99% CI, 0.72-0.79). When compared with no medication, adding one more decreased the risk by approximately half (OR, 0.59; 99% CI, 0.55-0.62). Treatment with 3 or more medications further decreased the risk of presenting with STEMI (multiply adjusted OR, 0.48; 99% CI, 0.44-0.52) (Figure 2), although this group included only a small proportion of the patients. Effects were consistent regardless of age and sex.
Despite a higher risk of presenting with ST-segment elevation, mortality risk did not decrease with the number of medications; 30-day mortality in non-STEMI patients receiving no medications was 5.5% and in STEMI patients was 7.9%, increasing to 8.3% in non-STEMI patients and 13.5% in STEMI patients receiving 2 medications. In patients receiving 3 or more medications, 30-day mortality was 5.9% and 10.3% in non-STEMI and STEMI patients, respectively.
In this study with data from a large national register that included more than 100 000 patients with a first AMI, previous medication use (ie, aspirin, β-blockers, ACE inhibitors, or statins) was associated with a decreased risk of presenting with STEMI. In addition, the risk decreased with the number of these medications used before AMI. These findings could be useful in explaining some of the beneficial effects of these medications on coronary mortality demonstrated in several randomized controlled trials.
We are aware of few studies that systematically compared medications in patients with different manifestations of coronary disease. In 1 recent study, it was found that the use of statins and β-blockers in adults whose first clinical presentation of coronary disease was AMI or stable exertional angina was associated with lower odds of presenting with an AMI than with stable angina, suggesting that these agents may stabilize the underlying coronary plaque.8 The same mechanisms potentially apply in ST-segment elevation vs no ST-segment elevation in AMI. In the Global Registry of Acute Coronary Events (GRACE) Study, patients with ACS who received long-term aspirin therapy were significantly less likely to have STEMI (OR, 0.35; 95% CI, 0.30-0.40) compared with patients not taking aspirin.10 The GRACE Study further demonstrated that patients receiving statins before admission were less likely to present with STEMI (OR, 0.79; 95% CI, 0.71-0.88).9
These data are consistent with our findings. However, we were able to expand on these previous results by finding a similar effect for ACE inhibitors and β-blockers and, furthermore, to demonstrate that these effects seem to be additive, with less risk of STEMI correlated with the use of more medications.
In general, ST-segment elevation results from transmural acute myocardial ischemia in response to fissuring or rupture of an atheromatous plaque, with total and prolonged occlusion of a major coronary artery. In contrast, non–ST-segment elevation in the setting of ACS is usually associated with incomplete coronary occlusion or occlusion of a small branch artery. Preexisting disease is important in that the existence of prior collateral flow in the affected artery may limit the spread of necrosis, preserving the subpericardial zone.13 Research in patients with ACS or a first episode of AMI has shown that the risk of presenting with STEMI was strongly associated with smoking,14,15 whereas prior disease (eg, angina, prior MI, percutaneous coronary intervention, and coronary artery bypass graft)14 and hypertension15 are associated with less ST-segment elevation.14 Similarly, in the GRACE Study, a history of angina, MI, stroke, or myocardial revascularization was more frequent among patients with unstable angina than among those with MI and was more common among patients with non-STEMI than among those with STEMI. These findings suggest that not only can prior disease and other factors influence prognosis, they may also modify the disease process and clinical presentation.
To what extent our findings reflect the pharmacological effects of the investigated medications or simply are associated with more preexisting and advanced disease in non-STEMI patients and consequently use of more medications cannot be determined by this cross-sectional study. However, we did control for age and several other medical conditions known to be associated with a lower risk of presenting with ST-segment elevation. The strong and independent effect (lowering the risk of presenting with ST-segment elevation by 15% to 25% for each medication) makes it unlikely that the use of these agents reflects only the presence of more advanced disease. The effect on risk of ST-segment elevation did not translate into lower short-term mortality, which is the net result of a multitude of different influences (not least of these being age and comorbidities, which are associated with lower risk of STEMI but higher risk of death after AMI).
The medicines in the present study have well-documented effects, persuasively proved in a large number of trials and surveys, and have been shown to lower the risk of cardiovascular disease. However, the mechanisms by which they protect from adverse cardiovascular outcomes are quite different for the various agents we investigated. Aspirin has a well-documented antiplatelet or anticlotting effect.16 Accordingly, the protection from transmural ischemia through this antithrombotic effect is a probable mechanism. β-Blockers reduce the cardiac rate and myocardial metabolic demand, resulting in lower oxygen demand, less widespread infarction, and documented effects on survival.17 Angiotensin-converting enzyme inhibitors have been shown to exert cardioprotective effects by reducing myocardial and vascular hypertrophy.18- 20 Moreover, early initiation of ACE inhibitor therapy reduces mortality in STEMI patients.19 Finally, ACE inhibitors probably have a vascular protective effect by influencing atherosclerosis progression and plaque rupture, thereby reducing the cardiovascular mortality in high-risk patients. However, the mechanisms involved are not clear.20
A large number of studies have demonstrated the benefit of treatment to lower lipid levels in primary and secondary prevention of cardiovascular disease.21,22 Early statin treatment is also associated with reduced mortality in patients with ACS,23 although there is limited evidence of the benefits of use of statin therapy in AMI. Previously, data from the Swedish Register of Cardiac Intensive Care showed that early initiation of statin treatment in patients with AMI is associated with reduced 1-year mortality.11 Data from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study demonstrated that immediate atorvastatin calcium therapy in patients with ACS was associated with reduced recurrent ischemia.24 In addition to the effects of lowering total serum cholesterol levels and slowing the progression and promoting the regression of coronary atherosclerosis,25 statins have demonstrated a number of other positive effects. Such pleiotropic effects, which include anti-inflammatory, antithrombotic, and plaque stabilization effects, may help to explain our findings.26,27
From these and other data, it appears that previous use of medications may exert several effects on the coronary arteries, leading to less risk of transmural ischemia in AMI. Furthermore, with an increasing number of medications, the risk of STEMI decreased. With more restrictive thresholds for what is considered normal or desirable levels of blood pressure and serum lipid levels—notably, serum cholesterol levels—a larger proportion in the population is likely to be treated with ACE inhibitors, β-blockers, or statins. According to our findings, this may have contributed to the declining severity in incident MI as reported in the Atherosclerosis Risk in Communities Study, which, with carefully documented methods, demonstrated a 2% yearly decline in the proportion of patients with AMI presenting with initial ST-segment elevation.28 The authors noted that increasing knowledge about the benefits of primary prevention may have influenced the use of aspirin, β-blockers, and statins, but because they had no information on preadmission medication use and preexisting medical conditions, this hypothesis could not be tested in their data set. In our study population, the proportion of patients presenting with ST-segment elevation decreased during the study period. Concomitantly, there was an increase in the proportion of patients using medications. However, all multivariable analyses included year of admission.
Our study had several strong points. We studied a large, nationally representative population from a quality-of-care register (ie, the RIKS-HIA) with high coverage levels. More than 95% of all patients admitted to a coronary care unit in Sweden are currently included in the RIKS-HIA. However, only patients surviving long enough to be admitted could be included.
In 2001, the diagnostic criteria for MI were changed, with a lower limit for creatine kinase–MB fraction.12 Patients who previously would have been diagnosed as having unstable angina pectoris in later years received a non-STEMI diagnosis. This fact would have contributed to a larger proportion of non-STEMI patients during the later part of the study. Even so, the effect of any of the 4 types of medication was strong and independent of the year of hospitalization.
A third limitation is that medications may simply reflect more severe underlying disease, which in itself would lead to less risk of developing STEMI. However, we did control for several premorbid conditions, with a persisting strong effect of all types of medication. Therefore, we believe it is unlikely that residual confounding could account for our findings in any major way.
In conclusion, among patients in the RIKS-HIA register presenting with a first AMI, previous treatment with aspirin, β-blockers, ACE inhibitors, and statins was substantially associated with less risk of presenting with STEMI, a more damaging and severe AMI. This finding held in men and women regardless of age. The risk decreased with the number of medications used before the AMI. Increasing use of preventive medications in the population could contribute to decreasing severity in AMI, further emphasizing the importance of medical treatment in patients perceived to be at high risk.
Correspondence: Lena Björck, PhD, Department of Medicine, Sahlgrenska University Hospital/Östra, SE-416 85 Göteborg, Sweden (email@example.com).
Accepted for Publication: January 31, 2010.
Author Contributions:Study concept and design: Björck, Wallentin, Lappas, and Rosengren. Acquisition of data: Björck, Wallentin, Stenestrand, and Lappas. Analysis and interpretation of data: Björck, Lappas, and Rosengren. Drafting of the manuscript: Björck and Rosengren. Critical revision of the manuscript for important intellectual content: Björck, Wallentin, Stenestrand, Lappas, and Rosengren. Statistical analysis: Björck and Lappas. Obtained funding: Wallentin and Rosengren. Administrative, technical, and material support: Björck, Wallentin, Stenestrand, Lappas, and Rosengren. Study supervision: Wallentin and Rosengren.
Financial Disclosure: None reported.
Funding/Support: This study was supported by EpiLife (Göteborg Center for Epidemiologic Studies on Mental and Physical Health Interacting Over the Lifecourse) (http://www.epilife.sahlgrenska.gu.se) and was financed by the Swedish Council for Working Life and Social Research; and by grants from the Swedish Heart and Lung Foundation and the Swedish Research Council.